Acute sinusitis is one of the most common diagnoses for which antimicrobials are prescribed for children in the US. Yet, available literature and our preliminary data suggest that only a subset of children diagnosed as having acute sinusitis based on current clinical criteria are likely to have bacterial disease. This finding, which is not entirely surprising, reflects the large overlap between symptoms and signs of an uncomplicated viral upper respiratory tract infection (URI) and acute bacterial sinusitis. Accordingly, in a population of children diagnosed as having acute sinusitis, response to antimicrobials is likely to be heterogeneous; those with true bacterial disease are likely to benefit substantially from antimicrobial therapy whereas those without bacterial disease would derive no benefit. The aim of this study is to identify subgroups of children who meet current diagnostic criteria for acute sinusitis, but in whom antimicrobial therapy provides no benefit. This objective will be achieved by conducting a large, randomized, double-blind, placebo-controlled clinical trial in children 2 to 12 years of age with persistent or worsening presentations of acute sinusitis. Children will be randomized to receive amoxicillin-clavulanate or placebo. Based on preliminary data we have gathered, we hypothesize that the subgroup of children who harbor no respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis) in their nasopharynx, and the subgroup of children whose nasal discharge is grossly clear, are unlikely to have bacterial disease and therefore will not benefit from antimicrobial therapy. Innovations that will differentiate this study from previous studies include: 1) an experienced multidisciplinay research team working in a multicenter setting; 2) use of a well-validated measure of outcome; 3) use of electronic diaries to minimize the amount of missing data; and 4) a priori identification of subgroups likely to respond differently to antimicrobial therapy. Should the proposed hypotheses be borne out, clinicians would be provided a basis for restricting antimicrobial use to specific subgroups of children who are most likely to benefit from it. Reduction of unnecessary antimicrobial use constitutes an important contribution to both individual and public health and is in accord with our long-term goal and that of NIAID. Absent a study of this nature, it seems likely that many children with uncomplicated viral URI will continue to be treated inappropriately with antimicrobials. This trial will offer a departure from an all-or-none approach to decision-making regarding antimicrobials for acute sinusitis, and permit a more nuanced, evidence-based approach.